The proposed research involves the development of radiopharmaceuticals that localize in the brain of Alzheimer's disease (AD) subjects bases upon their selective binding to beta- sheet fibrils such as those found in amyloid-beta protein (Abeta). The deposition of amyloid protein in brain is believed to play a key role in the pathogenesis of AD. At present, no method is capable of directly assessing the amount of amyloid deposited in the brains of living human subjects. Our plan is to rationally design and synthesize selective and potent amyloid- binding radioliglands capable of penetrating the blood-brain barrier and selectively binding to amyloid deposits with high affinity. The structure of these radioligands is based upon lead compounds distantly-related chemically to the classic amyloid stains Congo red and Thioflavin-T. It is anticipated that the application of the proposed amyloid radioligands will make possible the first direct assessment of cerebral amyloid burden and response to therapeutic strategies aimed at halting or reversing amyloid deposition in the brains of human subjects. Our specific aims include: 1) rationally design, synthesize, and evaluate the in vitro properties of a selected array of amyloid- binding agents; 2) radiolabel the most promising compounds with the positron-emitting radionuclides 11C or 18F; 3) assess the in vivo properties of these radiotracers in transgenic mouse models of amyloid plaque deposition to determine the absolute brain uptake of the agents, radiotracer clearance, and specific retention of the radiotracer in rodent brain containing high densities of amyloid plaques; and 4) assess the in vivo properties of the radiotracers in normal control baboons using positron emission tomography (PET) imaging to determine the peripheral metabolism and pharmacokinetics of the compounds in non-human primate brain prior to initiating studies in human subjects.